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Heydarian, M. ; Oak, P. ; Zhang, X. ; Kamgari, N. ; Kindt, A.S.D.* ; Koschlig, M. ; Pritzke, T. ; Gonzalez-Rodriguez, E. ; Förster, K. ; Morty, R.E.* ; Häfner, F. ; Hübener, C.* ; Flemmer, A.W.* ; Yildirim, A.Ö. ; Sudheendra, D.* ; Tian, X.* ; Petrera, A. ; Kirsten, H.* ; Ahnert, P.* ; Morrell, N.* ; Desai, T.J.* ; Sucre, J.* ; Spiekerkoetter, E.* ; Hilgendorff, A.

Relationship between impaired BMP signalling and clinical risk factors at early-stage vascular injury in the preterm infant.

Thorax 77, 1176-1186 (2022)

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INTRODUCTION: Chronic lung disease, that is, bronchopulmonary dysplasia (BPD) is the most common complication in preterm infants and develops as a consequence of the misguided formation of the gas-exchange area undergoing prenatal and postnatal injury. Subsequent vascular disease and its progression into pulmonary arterial hypertension critically determines long-term outcome in the BPD infant but lacks identification of early, disease-defining changes. METHODS: We link impaired bone morphogenetic protein (BMP) signalling to the earliest onset of vascular pathology in the human preterm lung and delineate the specific effects of the most prevalent prenatal and postnatal clinical risk factors for lung injury mimicking clinically relevant conditions in a multilayered animal model using wild-type and transgenic neonatal mice. RESULTS: We demonstrate (1) the significant reduction in BMP receptor 2 (BMPR2) expression at the onset of vascular pathology in the lung of preterm infants, later mirrored by reduced plasma BMP protein levels in infants with developing BPD, (2) the rapid impairment (and persistent change) of BMPR2 signalling on postnatal exposure to hyperoxia and mechanical ventilation, aggravated by prenatal cigarette smoke in a preclinical mouse model and (3) a link to defective alveolar septation and matrix remodelling through platelet derived growth factor-receptor alpha deficiency. In a treatment approach, we partially reversed vascular pathology by BMPR2-targeted treatment with FK506 in vitro and in vivo. CONCLUSION: We identified impaired BMP signalling as a hallmark of early vascular disease in the injured neonatal lung while outlining its promising potential as a future biomarker or therapeutic target in this growing, high-risk patient population.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Paediatric Lung Disaese

ISSN (print) / ISBN 0040-6376

e-ISSN 1468-3296

Journal Thorax

Quellenangaben Volume: 77, Issue: 12, Pages: 1176-1186

Publisher BMJ Publishing Group

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Lung Health and Immunity (LHI)
Institute of Lung Biology (LHI)
CF Metabolomics & Proteomics (CF-MPC)

Grants Helmholtz Zentrum Munchen
Deutsches Zentrum für Lungenforschung
Helmholtz Association
Bundesministerium für Bildung und Forschung
Deutsche Forschungsgemeinschaft
German Ministry of Education and Health